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Abstract Background Caesarean section (CS) rates are rising worldwide. In the Netherlands, the most significant rise is observed in healthy women with a singleton in vertex position between 37 and 42 weeks gestation, whereas it is doubtful whether an improved outcome for the mother or her child was obtained. It can be hypothesized that evidence-based guidelines on CS are not implemented sufficiently. Therefore, the present study has the following objectives: to develop quality indicators on the decision to perform a CS based on key recommendations from national and international guidelines; to use the quality indicators in order to gain insight into actual adherence of Dutch gynaecologists to guideline recommendations on the performance of a CS; to explore barriers and facilitators that have a direct effect on guideline application regarding CS; and to develop, execute, and evaluate a strategy in order to reduce the CS incidence for a similar neonatal outcome (based on the information gathered in the second and third objectives). Methods An independent expert panel of Dutch gynaecologists and midwives will develop a set of quality indicators on the decision to perform a CS. These indicators will be used to measure current care in 20 hospitals with a population of 1,000 women who delivered by CS, and a random selection of 1,000 women who delivered vaginally in the same period. Furthermore, by interviewing healthcare professionals and patients, the barriers and facilitators that may influence the decision to perform a CS will be measured. Based on the results, a tailor-made implementation strategy will be developed and tested in a controlled before-and-after study in 12 hospitals (six intervention, six control hospitals) with regard to effectiveness, experiences, and costs. Discussion This study will offer insight into the current CS care and into the hindering and facilitating factors influencing obstetrical policy on CS. Furthermore, it will allow definition of patient categories or situations in which a tailor-made implementation strategy will most likely be meaningful and cost effective, without negatively affecting the outcome for mother and child. Trial registration http://www.clinicaltrials.gov: NCT01261676

Abstract Background Pain relief during labour is a topic of major interest in the Netherlands. Epidural analgesia is considered to be the most effective method of pain relief and recommended as first choice. However its uptake by pregnant women is limited compared to other western countries, partly as a result of non-availability due to logistic problems. Remifentanil, a synthetic opioid, is very suitable for patient controlled analgesia. Recent studies show that epidural analgesia is superior to remifentanil patient controlled analgesia in terms of pain intensity score; however there was no difference in satisfaction with pain relief between both treatments. Methods/design The proposed study is a multicentre randomized controlled study that assesses the cost-effectiveness of remifentanil patient controlled analgesia compared to epidural analgesia. We hypothesize that remifentanil patient controlled analgesia is as effective in improving pain appreciation scores as epidural analgesia, with lower costs and easier achievement of 24 hours availability of pain relief for women in labour and efficient pain relief for those with a contraindication for epidural analgesia. Eligible women will be informed about the study and randomized before active labour has started. Women will be randomly allocated to a strategy based on epidural analgesia or on remifentanil patient controlled analgesia when they request pain relief during labour. Primary outcome is the pain appreciation score, i.e. satisfaction with pain relief. Secondary outcome parameters are costs, patient satisfaction, pain scores (pain-intensity), mode of delivery and maternal and neonatal side effects. The economic analysis will be performed from a short-term healthcare perspective. For both strategies the cost of perinatal care for mother and child, starting at the onset of labour and ending ten days after delivery, will be registered and compared. Discussion This study, considering cost effectiveness of remifentanil as first choice analgesia versus epidural analgesia, could strongly improve the care for 180.000 women, giving birth in the Netherlands yearly by giving them access to pain relief during labour, 24 hours a day. Trial registration number Dutch Trial Register NTR2551, http://www.trialregister.nl

Abstract Background One of the most commonly reported problems of randomised trials is that recruitment is usually slower than expected. Trials will cost more and take longer, thus delaying the use of the results in clinical practice, and incomplete samples imply decreased statistical power and usefulness of its results. We aim to identify barriers and facilitators for successful patient recruitment at the level of the patient, the doctor and the hospital organization as well as the organization and design of trials over a broad range of studies. Methods/design We will perform two cohort studies and a case-control study in the Netherlands. The first cohort study will report on a series of multicenter trials performed in a nationwide network of clinical trials in obstetrics and gynaecology. A questionnaire will be sent to all clinicians recruiting for these trials to identify determinants - aggregated at centre level - for the recruitment rate. In a case control-study nested in this cohort we will interview patients who refused or consented participation to identify factors associated with patients' consent or refusal. In a second cohort study, we will study trials that were prospectively registered in the Netherlands Trial Register. Using a questionnaire survey we will assess whether issues on hospital organization, trial organization, planning and trial design were associated with successful recruitment, i.e. 80% of the predefined number of patients recruited within the planned time. Discussion This study will provide insight in barriers and facilitators for successful patient recruitment in trials. The results will be used to provide recommendations and a checklist for individual trialists to identify potential pitfalls for recruitment and judge the feasibility prior to the start of the study. Identified barriers and motivators coupled to evidence-based interventions can improve recruitment of patients in clinical trials.

Abstract Background Hypoxic-ischaemic encephalopathy is associated with development of cerebral palsy and cognitive disability later in life and is therefore one of the fundamental problems in perinatal medicine. The xanthine-oxidase inhibitor allopurinol reduces the formation of free radicals, thereby limiting the amount of hypoxia-reperfusion damage. In case of suspected intra-uterine hypoxia, both animal and human studies suggest that maternal administration of allopurinol immediately prior to delivery reduces hypoxic-ischaemic encephalopathy. Methods/Design The proposed trial is a randomized double blind placebo controlled multicenter study in pregnant women at term in whom the foetus is suspected of intra-uterine hypoxia. Allopurinol 500 mg IV or placebo will be administered antenatally to the pregnant woman when foetal hypoxia is suspected. Foetal distress is being diagnosed by the clinician as an abnormal or non-reassuring foetal heart rate trace, preferably accompanied by either significant ST-wave abnormalities (as detected by the STAN-monitor) or an abnormal foetal blood scalp sampling (pH < 7.20). Primary outcome measures are the amount of S100B (a marker for brain tissue damage) and the severity of oxidative stress (measured by isoprostane, neuroprostane, non protein bound iron and hypoxanthine), both measured in umbilical cord blood. Secondary outcome measures are neonatal mortality, serious composite neonatal morbidity and long-term neurological outcome. Furthermore pharmacokinetics and pharmacodynamics will be investigated. We expect an inclusion of 220 patients (110 per group) to be feasible in an inclusion period of two years. Given a suspected mean value of S100B of 1.05 ug/L (SD 0.37 ug/L) in the placebo group this trial has a power of 90% (alpha 0.05) to detect a mean value of S100B of 0.89 ug/L (SD 0.37 ug/L) in the 'allopurinol-treated' group (z-test2-sided). Analysis will be by intention to treat and it allows for one interim analysis. Discussion In this trial we aim to answer the question whether antenatal allopurinol administration reduces hypoxic-ischaemic encephalopathy in neonates exposed to foetal hypoxia. Trial registration number Clinical Trials, protocol registration system: NCT00189007

Abstract Background Preterm labour is the main cause of perinatal morbidity and mortality in the Western world. At present, there is evidence that tocolysis for 48 hours is useful in women with threatened preterm labour at least before 32 weeks. This allows transfer of the patient to a perinatal centre, and maximizes the effect of corticosteroids for improved neonatal survival. It is questionable whether treatment with tocolytics should be maintained after 48 hours. Methods/Design The APOSTEL II trial is a multicentre placebo-controlled study. Pregnant women admitted for threatened preterm labour who have been treated with 48 hours corticosteroids and tocolysis will be eligible to participate in the trial between 26+0 and 32+2 weeks gestational age. They will be randomly allocated to nifedipine (intervention) or placebo (control) for twelve days or until delivery, whatever comes first. Primary outcome is a composite of perinatal death, and severe neonatal morbidity up to evaluation at 6 months after birth. Secondary outcomes are gestational age at delivery, number of days in neonatal intensive care and total days of the first 6 months out of hospital. In addition a cost-effectiveness analysis will be performed. Analysis will be by intention to treat. The power calculation is based on an expected 11% difference in adverse neonatal outcome. This implies that 406 women have to be randomised (two sided test, β 0.2 at alpha 0.05). Discussion This trial will provide evidence as to whether maintenance tocolysis reduces severe perinatal morbidity and mortality in women with threatened preterm labour before 32 weeks. Trial Registration Clinical trial registration: http://www.trialregister.nl, NTR 1336, date of registration: June 3rd 2008.

Abstract Background At present, women with threatened preterm labor before 32 weeks of gestation are, after transfer to a perinatal center, treated with tocolytics and corticosteroids. Many of these women are treated unnecessarily. Fibronectin is an accurate predictor for the occurrence of preterm birth among women with threatened preterm labor. We will assess whether triage of these women with fibronectin testing, cervical length or their combination is cost-effective. Methods/Design We will investigate a prospective cohort of women referred to a perinatal centre for spontaneous threatened preterm labor between 24 and 34 weeks with intact membranes. All women will be tested for fibronectin and cervical length. Women with a cervical length 30 mm will be managed according to local protocol. Corticosteroids may be given to all women at the discretion of the attending physician. Primary outcome measure will be delivery within 7 days. Secondary outcome measures will be neonatal morbidity and mortality, complications of tocolytics, costs and health related quality of life. The analysis will be according to the intention to treat principle. We anticipate the probability on preterm birth within 7 days in the group of women with a negative fibronectine test to be 5%. Two groups of 110 women will be needed to assure that in case of non-inferiority the difference in the proportion of preterm deliveries < 7 days will be within a prespecified boundary of 7.5% (one sided test, β 0.2, α 0.05). Data obtained from women with a positive and negative fibronectin tests in both the cohort study and the trial will be integrated in a cost-effectiveness analysis that will assess economic consequences of the use of fibronectin. Discussion This study will provide evidence for the use of fibronectin testing as safe and cost-effective method in a triage for threatened preterm labor. Trial registration Nederlands Trial Register (NTR) number 1857, http://www.trialregister.nl.

Abstract Background Preterm prelabour rupture of the membranes (PPROM) is an important clinical problem and a dilemma for the gynaecologist. On the one hand, awaiting spontaneous labour increases the probability of infectious disease for both mother and child, whereas on the other hand induction of labour leads to preterm birth with an increase in neonatal morbidity (e.g., respiratory distress syndrome (RDS)) and a possible rise in the number of instrumental deliveries. Methods/Design We aim to determine the effectiveness and cost-effectiveness of immediate delivery after PPROM in near term gestation compared to expectant management. Pregnant women with preterm prelabour rupture of the membranes at a gestational age from 34+0 weeks until 37+0 weeks will be included in a multicentre prospective randomised controlled trial. We will compare early delivery with expectant monitoring. The primary outcome of this study is neonatal sepsis. Secondary outcome measures are maternal morbidity (chorioamnionitis, puerperal sepsis) and neonatal disease, instrumental delivery rate, maternal quality of life, maternal preferences and costs. We anticipate that a reduction of neonatal infection from 7.5% to 2.5% after induction will outweigh an increase in RDS and additional costs due to admission of the child due to prematurity. Under these assumptions, we aim to randomly allocate 520 women to two groups of 260 women each. Analysis will be by intention to treat. Additionally a cost-effectiveness analysis will be performed to evaluate if the cost related to early delivery will outweigh those of expectant management. Long term outcomes will be evaluated using modelling. Discussion This trial will provide evidence as to whether induction of labour after preterm prelabour rupture of membranes is an effective and cost-effective strategy to reduce the risk of neonatal sepsis. Controlled clinical trial register ISRCTN29313500

Abstract Background Cardiotocography (CTG) is worldwide the method for fetal surveillance during labour. However, CTG alone shows many false positive test results and without fetal blood sampling (FBS), it results in an increase in operative deliveries without improvement of fetal outcome. FBS requires additional expertise, is invasive and has often to be repeated during labour. Two clinical trials have shown that a combination of CTG and ST-analysis of the fetal electrocardiogram (ECG) reduces the rates of metabolic acidosis and instrumental delivery. However, in both trials FBS was still performed in the ST-analysis arm, and it is therefore still unknown if the observed results were indeed due to the ST-analysis or to the use of FBS in combination with ST-analysis. Methods/Design We aim to evaluate the effectiveness of non-invasive monitoring (CTG + ST-analysis) as compared to normal care (CTG + FBS), in a multicentre randomised clinical trial setting. Secondary aims are: 1) to judge whether ST-analysis of fetal electrocardiogram can significantly decrease frequency of performance of FBS or even replace it; 2) perform a cost analysis to establish the economic impact of the two treatment options. Women in labour with a gestational age ≥ 36 weeks and an indication for CTG-monitoring can be included in the trial. Eligible women will be randomised for fetal surveillance with CTG and, if necessary, FBS or CTG combined with ST-analysis of the fetal ECG. The primary outcome of the study is the incidence of serious metabolic acidosis (defined as pH < 7.05 and Bdecf > 12 mmol/L in the umbilical cord artery). Secondary outcome measures are: instrumental delivery, neonatal outcome (Apgar score, admission to a neonatal ward), incidence of performance of FBS in both arms and cost-effectiveness of both monitoring strategies across hospitals. The analysis will follow the intention to treat principle. The incidence of metabolic acidosis will be compared across both groups. Assuming a reduction of metabolic acidosis from 3.5% to 2.1 %, using a two-sided test with an alpha of 0.05 and a power of 0.80, in favour of CTG plus ST-analysis, about 5100 women have to be randomised. Furthermore, the cost-effectiveness of CTG and ST-analysis as compared to CTG and FBS will be studied. Discussion This study will provide data about the use of intrapartum ST-analysis with a strict protocol for performance of FBS to limit its incidence. We aim to clarify to what extent intrapartum ST-analysis can be used without the performance of FBS and in which cases FBS is still needed. Trial Registration Number ISRCTN95732366

Background The value of ST analysis of the fetal electrocardiogram during labor to lower asphyxia and cesarean section rates is uncertain. Physiological variation of the electrical heart axis between fetuses may explain false alarms in conventional ST analysis (absolute ST analysis). ST events (alarms) based on relative T/QRS rises (relative ST analysis) correct for this variation and may improve diagnostic accuracy of ST analysis. Aims To compare the diagnostic accuracy of absolute and relative ST analysis with regard to fetal acidemia. Study design Retrospective case-control study. Subjects 20 healthy women with an uncomplicated pregnancy monitored with ST analysis during labor: 10 cases (umbilical cord artery pH < 7.05) and 10 controls (pH > 7.20). Outcome measures Sensitivity, specificity, positive and negative likelihood ratio. Results In 16 of the 20 patients a total of 54 absolute ST events were reported. Two reviewers classified the cardiotocograms; in cases 29% of the absolute ST events were significant, in the controls it was 19%. Relative ST analysis versus absolute ST analysis showed a sensitivity of 90% (55−100%) vs. 70% (35−93%), a specificity of 100% (69–100%) vs. 70% (35−93%), a positive likelihood ratio of infinity vs. 2.3 (0.8−6.5), a negative likelihood ratio of 0.1 (0.0−0.6) vs. 0.4 (0.2−1.2), and diagnostic odds ratio of infinity vs. 5.4 (0.8−36.9). McNemar showed no statistical significant difference between the sensitivity and specificity of the methods. Conclusions We observed higher positive and lower negative likelihood ratios for relative ST analysis in comparison to absolute ST analysis. In this small study we found no statistical difference. Relative ST analysis should be studied in a larger study. [ABSTRACT FROM AUTHOR]

Introduction: There is little evidence to guide the timing of delivery of women with early-onset severe preeclampsia. We hypothesize that immediate delivery is not inferior for neonatal outcome but reduces maternal complications compared with temporizing management.Material and Methods: This Dutch multicenter open-label randomized clinical trial investigated non-inferiority for neonatal outcome of temporizing management as compared with immediate delivery (TOTEM NTR 2986) in women between 27+5 and 33+5 weeks of gestation admitted for early-onset severe preeclampsia with or without HELLP syndrome. In participants allocated to receive immediate delivery, either induction of labor or cesarean section was initiated at least 48 hours after admission. Primary outcomes were adverse perinatal outcome, defined as a composite of severe respiratory distress syndrome, bronchopulmonary dysplasia, culture proven sepsis, intraventricular hemorrhage grade 3 or worse, periventricular leukomalacia grade 2 or worse, necrotizing enterocolitis stage 2 or worse, and perinatal death. Major maternal complications were secondary outcomes. It was estimated 1130 women needed to be enrolled. Analysis was by intention-to-treat.Results: The trial was halted after 35 months because of slow recruitment. Between February 2011 and December 2013, a total of 56 women were randomized to immediate delivery (n = 26) or temporizing management (n = 30). Median gestational age at randomization was 30 weeks. Median prolongation of pregnancy was 2 days (interquartile range 1-3 days) in the temporizing management group. Mean birthweight was 1435 g after immediate delivery vs 1294 g after temporizing management (P = .14). The adverse perinatal outcome rate was 55% in the immediate delivery group vs 52% in the temporizing management group (relative risk 1.06; 95% confidence interval 0.67-1.70). In both groups there was one neonatal death and no maternal deaths. In the temporizing treatment group, one woman experienced pulmonary edema and one placental abruption. Analyses of only the singleton pregnancies did not result in other outcomes.Conclusions: Early termination of the trial precluded any conclusions for the main outcomes. We observed that temporizing management resulted in a modest prolongation of pregnancy without changes in perinatal and maternal outcome. Conducting a randomized study for this important research question did not prove feasible. [ABSTRACT FROM AUTHOR]